Ketamine and the Dissociatives

Dissociative agents—uncompetitive N -methyl- d -aspartate receptor (NMDAR) antagonists—such as ketamine, phencyclidine, and dizocilpine are known to transiently induce positive, negative, and cognitive symptoms of schizophrenia in healthy adults. Herein, we conclude that dissociative drug challenge accurately models neurotransmitter dysfunction, excitotoxicity, neurodegeneration, age of onset, gamma band aberrations, and electroencephalogram signal complexity observed in schizophrenia. Furthermore, dissociative drugs bind to a host of other receptors (e.g., sigma, opioid, dopamine D 2 , cholinergic) and thus transcend NMDAR hypofunction models of schizophrenia. Principal effects of dissociative agents are mediated by blockade of NMDARs expressed by gamma-aminobutyric acid (GABA)ergic interneurons, resulting in disruptions of gamma oscillations and disinhibition of glutamatergic and cholinergic afferents, triggering patterns of excitotoxic neurodegeneration seen in schizophrenia. Future work should seek to understand the extent to which ketamine and other dissociative drugs might effect psychomimesis through action at muscarinic, nicotinic, opioid, and sigma-1 receptors, as well as monoamine transporters.